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Background/Aims

Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).

Methods

Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.

Results

In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.

Conclusions

In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.

This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m2 estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m2 estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.

OBJECTIVE

Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population.

RESEARCH DESIGN AND METHODS

This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples.

RESULTS

Of 691 participants, 378 died over 10 years of follow-up. Cystatin C–estimated GFR <60 ml/min per 1.73 m2, creatinine-based estimated GFR <60 ml/min per 1.73 m2, and urine ACR ≥30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95% CI 1.37–2.18), 1.54 (1.21–1.97), and 1.73 (1.39–2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C–estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C–estimated GFR predicted mortality more strongly than creatinine-based estimated GFR.

CONCLUSIONS

Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.

Background. Kidney disease is a risk factor for mortality and cardiovascular disease in older adults, but the separate and combined effects of albuminuria and cystatin C, a novel marker of glomerular filtration, are not known.

Methods. We examined associations of these markers with mortality and cardiovascular outcomes during a median follow-up of 8.3 years in 3291 older adults in the Cardiovascular Health Study. Kidney disease was assessed using urinary albumin/creatinine ratio (ACR), cystatin C and Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR). We defined subgroups based on presence of microalbuminuria (MA, ACR > 30 mg/g) and categories of normal kidney function (cystatin C < 1.0 mg/L and eGFR > 60 mL/min/1.73 m2); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m2); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m2). Cox proportional hazards models were used to examine associations between these six subgroups and all-cause or cardiovascular mortality, myocardial infarction and heart failure.

Results. One thousand one hundred fifty (34.9%) had normal kidney function (12.2% with MA), 1518 (46.1%) had preclinical kidney disease (17.9% with MA) and 622 (18.9%) had CKD (47% with MA). After adjustment, the presence of either preclinical kidney disease or MA was associated with an over 50% increase in mortality risk; the presence of both was associated with a 2.4-fold mortality risk. Those with CKD and MA were at highest risk, with a nearly 4-fold mortality risk.

Conclusion. Elevated cystatin C and albuminuria are common, identify different subsets of the older population, and are independent, graded risk factors for cardiovascular disease and mortality.

Background:

The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate.

Methods:

These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006.

Results:

A total of 390 participants had an incident stroke: 81% ischemic, 12% hemorrhagic, and 7% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95% confidence interval [CI] 1.47-3.00), while HR for eGFR was 1.29 (95% CI 0.91-1.84) and for cystatin C was 1.22 (95% CI 0.85-1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories.

Conclusions:

UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.

GLOSSARY

= atrial fibrillation;

= Cardiovascular Health Study;

= confidence interval;

= estimated glomerular filtration rate;

= hazard ratio;

= left ventricular hypertrophy;

= urinary albumin-to-creatinine ratio.

Background

Research on the relationship between urinary albumin excretion and serum cystatin C in diabetes is restricted to cross-sectional studies. In this study, we investigated how well serial measurements of serum cystatin C level reflect changes in the urinary albumin excretion rate.

Methods

We enrolled and retrospectively collected data on 1,058 participants with type 2 diabetes who were older than 18 years and who had more than 3 years of follow-up with serial measurements of albuminuria and serum cystatin C at an outpatient clinic.

Results

With the use of a linear mixed model, we found that the albuminuria level for each patient over time corresponded with the annual change in serum cystatin C-based estimated glomerular filtration rate (cysC-eGFR) but did not correspond with the creatinine-based eGFR calculated by the modification of diet in renal disease formula (MDRD-eGFR). The discrepancy in the direction of the trend was smaller with cysC-eGFR than with MDRD-eGFR.

Conclusion

Serum cystatin C level reflects the trend in albuminuria level more accurately than serum creatinine level in Korean type 2 diabetes mellitus patients.

Background. Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.

Methods. We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.

Results. The prevalence of moderate to severe kidney disease (eGFR 15–59 mL/min/1.73 m2) among anaemic persons was 15–16% when based on serum creatinine alone (eGFRSCR) or combined with cystatin C (eGFRSCR + CYSC); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFRCYSC). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFRCYSC than eGFRSCR and eGFRSCR + CYSC in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98–27.36).

Conclusions. Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFRCYSC may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.

Background

The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C and albuminuria with development of CKD stage 3.

Study Design

Prospective observational study.

Setting and Participants

5,422 participants from the Multi-Ethnic Study of Atherosclerosis with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2.

Predictor

Participants were categorized into four mutually exclusive groups: presence or absence of microalbuminuria (albumin-creatinine ratio >17 and > 25 µg/mg in men and women, respectively) in those with or without cystatin C ≥ 1.0 mg/L.

Outcomes and Measurements

Incident CKD stage 3 was defined as eGFR < 60 ml/min/1.73m2 at the 3rd or 4th visit and an annual decline of > 1 ml/min/1.73 m2. Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR.

Results

Mean age was 61 years, 49% were men, 38% white, 11% had diabetes, 13.7% had cystatin C ≥ 1mg/L, 8.4% had microalbuminuria, and 2.7 % had cystatin C ≥ 1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 over a median follow-up of 4.7 years and the adjusted incidence rate ratios (95% CI) were 1.57 (1.19–2.07), 1.37 (1.13–1.66), and 2.12 (1.61–2.80) in those with microalbuminuria, cystatin C ≥ 1 mg/L, and both, respectively, compared to those with neither.

Limitations

Relatively short follow up and absence of measured GFR.

Conclusions

Cystatin C and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk.

Background

Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.

Methods

In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.

Results

Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.

Conclusion

Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.

Background. The study was performed to investigate the prevalence, awareness and the risk factors of chronic kidney disease (CKD) in the community population in Shanghai, China.

Methods. A total of 2596 residents were randomly recruited from the community population in Shanghai, China. All were screened for albuminuria, haematuria, morning spot urine albumin-to-creatinine ratio and renal function. Serum creatinine, uric acid, cholesterol, triglyceride and haemoglobin were assessed. A simplified MDRD equation was used to estimate the glomerular filtration rate (eGFR). All studied subjects were screened by kidney ultrasound. Haematuria, if present in the morning spot urine dipstick test, was confirmed by microscopy. The associations among the demographic characteristics, health characteristics and indicators of kidney damage were examined.

Results. Two thousand five hundred and fifty-four residents (n = 2554), after giving informed consent and with complete data, were entered into this study. Albuminuria and haematuria were detected in 6.3% and 1.2% of all the studied subjects, respectively, whereas decreased kidney function was found in 5.8% of all studied subjects. Approximately 11.8% of subjects had at least one indicator of kidney damage. The rate of awareness of CKD was 8.2%. The logistic regression model showed that age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis each contributed to the development of CKD.

Conclusion. This is the first Shanghai community-based epidemiological study data on Chinese CKD patients. The prevalence of CKD in the community population in Shanghai is 11.8%, and the rate of awareness of CKD is 8.2%. All the factors including age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis are positively correlated with the development of CKD in our studied subjects.

Background

Although studies have reported a high prevalence of end-stage renal disease in human immunodeficiency virus (HIV)-infected individuals, little is known about moderate impairments in kidney function. Cystatin C measurement may be more sensitive than creatinine for detecting impaired kidney function in persons with HIV.

Methods

We evaluated kidney function in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort, a representative sample of 1008 HIV-infected persons and 290 controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study in the United States.

Results

Cystatin C level was elevated in HIV-infected individuals; the mean±SD cystatin C level was 0.92±0.22 mg/L in those infected with HIV and 0.76±0.15 mg/L in controls (P<.001). In contrast, both mean creatinine levels and estimated glomerular filtration rates appeared similar in HIV-infected individuals and controls (0.87±0.21 vs 0.85±0.19 mg/dL [to convert to micromoles per liter, multiply by 88.4] [P=.35] and 110±26 vs 106±23 mL/min/1.73 m2 [P=.06], respectively). Persons with HIV infection were more likely to have a cystatin C level greater than 1.0 mg/L (OR, 9.8; 95% confidence interval, 4.4-22.0 [P<.001]), a threshold demonstrated to be associated with increased risk for death and cardiovascular and kidney disease. Among participants with HIV, potentially modifiable risk factors for kidney disease, hypertension, and low high-density lipoprotein concentration were associated with a higher cystatin C level, as were lower CD4 lymphocyte count and coinfection with hepatitis C virus (all P<.001).

Conclusions

Individuals infected with HIV had substantially worse kidney function when measured by cystatin Clevel compared with HIV-negative controls, whereas mean creatinine levels and estimated glomerular filtration rates were similar. Cystatin C measurement could be a useful clinical tool to identify HIV-infected persons at increased risk for kidney and cardiovascular disease.

Background

Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.

Study Design

Cohort Study.

Setting & Participants

5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.

Predictor

The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).

Outcome

Infection-related hospitalizations during a median follow-up of 11.5 years.

Results

In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.

Limitations

No measures of urinary protein, study limited to principal discharge diagnosis.

Conclusions

Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.

Background

Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).

Methods

10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m2. Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.

Results

30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).

Conclusions

Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.

Background

Persons with early kidney disease have an increased risk of cardiovascular events and mortality, but the importance of accelerated atherosclerosis in promoting these outcomes is unclear. We therefore explored whether serum cystatin C level is associated with carotid intima-media thickness (IMT) in ambulatory adults without clinical heart disease.

Study Design

Cross-sectional study.

Setting & Participants

We evaluated 6,557 ethnically diverse persons free of clinical cardiovascular disease aged 45 to 84 years at the baseline visit of the Multi-Ethnic Study of Atherosclerosis.

Predictors

Kidney function was estimated by using 2 methods: serum cystatin C level and estimated glomerular filtration rate, based on creatinine and cystatin C levels.

Outcomes & Measurements

Study outcomes were internal and common carotid IMT, measured by using high-resolution B-mode ultrasound. Multivariate linear and logistic regressions were used to evaluate the independent association of kidney function with carotid IMT.

Results

In unadjusted linear analysis, each SD (0.23 mg/L) greater cystatin C level was associated with 0.091-mm greater internal carotid IMT (P < 0.001), but this association was diminished by 70% after adjustment for age, sex, and race/ethnicity (0.027 mm; P < 0.001) and was no longer significant after adjustment for cardiovascular risk factors (0.005 mm; P = 0.5). Similarly, the strong unadjusted associations of cystatin C level with common carotid IMT disappeared after adjustment. Chronic kidney disease, defined by using either creatinine level or cystatin C–based estimated glomerular filtration rate less than 60 mL/min/1.73 m2, had no independent association with internal and common carotid IMT.

Limitations

There were few participants with severe kidney disease.

Conclusions

Cystatin C level had no independent association with carotid IMT in a population free of clinical heart disease. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.

Background

Cystatin C is a marker of kidney function that may also be associated with inflammation. In this study, we compared the relative strengths of association of cystatin C and estimated glomerular filtration rate (eGFR) with inflammatory biomarkers.

Methods

We measured serum cystatin C and creatinine in 990 outpatients with coronary artery disease enrolled in the Heart and Soul Study. GFR was estimated (eGFR) by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. We compared the associations of serum cystatin C and eGFR with C-reactive protein (CRP) and fibrinogen, after adjustment for 24 h creatinine clearance.

Results

Cystatin C concentrations had moderate correlations with CRP (r=0.15, P<0.001) and fibrinogen (r=0.26, P<0.0001); eGFR had similar correlations with CRP (r=−0.17, P=0.01) and fibrinogen (r=−0.25, P<0.001) among persons with eGFR≤60 ml/min, but had no association with either biomarker among those with eGFR>60 ml/min (r=0.04, P=0.32; r=−0.03, P=0.38). Quartiles of cystatin C were strongly and directly associated with CRP (P=0.02) and fibrinogen (P<0.007) after multivariate adjustment. However, these associations disappeared after adjustment for creatinine clearance (P=0.26 and 0.23, respectively).

Conclusions

Cystatin C concentrations have moderate associations with CRP and fibrinogen that are not independent of creatinine clearance. Although a gold standard of kidney function is lacking, this analysis suggests that cystatin C captures an association of mildly impaired kidney function with increased inflammation.

Background/Aims

The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C.

Methods

In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 ± 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m2).

Results

Mean annual eGFR loss as estimated from creatinine was 0.4 ± 3.6 ml/min/1.73 m2, with 16% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 ± 2.6, with 25% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10% (n = 263) using creatinine and 19% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16–1.65), 1.62 (1.31–1.99) and 2.96 (2.28–3.84) for participants aged 70–74, 75–79 and 80+ at baseline, compared with those aged 65–69.

Conclusion

In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.

Aims

Serum cystatin C, a novel marker of kidney function, is reported to be superior to serum creatinine as a risk factor for atherosclerotic disease, but associations may vary across vascular beds.

Methods and results

A cross-sectional study of chronic kidney disease (CKD) and peripheral arterial disease (PAD) in 3089 adult participants aged 40+ from the 1999–2002 National Health and Nutrition Examination Survey (NHANES). Kidney function, assessed by estimated glomerular filtration rate (eGFR), was determined from serum creatinine and cystatin C using established equations. Peripheral arterial disease defined by an ankle brachial index <0.90. Glomerular filtration rate estimated using cystatin C was more strongly associated with PAD compared with eGFR using serum creatinine before and after multivariable adjustment. Further, after adjustment for cystatin C, kidney function based on serum creatinine was no longer significantly associated with PAD. However, cystatin C remained significantly associated with PAD even after adjustment for GFR estimated by serum creatinine. Compared with optimal kidney function (eGFRserum creatinine ≥60, eGFRcystatin C >90), the odds ratio for PAD was 3.11 (95% confidence interval 1.26–7.64) for preclinical CKD (eGFRserum creatinine ≥60, eGFRcystatin C <76.7) and 5.07 (3.01–8.52) for ‘confirmed’ CKD (eGFRserum creatinine <60, eGFRcystatin C <60).

Conclusion

Chronic kidney disease was strongly and independently associated with PAD. Cystatin C was a more potent marker of lower extremity PAD when compared with the serum creatinine equation currently used in clinical practice. Our results suggest that cystatin C may have clinical utility when combined with serum creatinine in evaluation of individuals who may have PAD.

In clinical practice the glomerular filtration rate (GFR) is estimated from serum creatinine-based equations like the Cockcroft-Gault formula (C&G) and Modification of Diet in Renal Disease formula (MDRD). Recently, serum cystatin C-based equations, the newer creatinine formula (The Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI)), and equation that use both serum creatinine and cystatin C (CKD-EPI creatinine & cystatin formula) were proposed as new GFR markers. Present study compares serum creatinine-based equations, combined (including both serum creatinine and cystatin C) equation, and serum simple cystatin C formula (100/serum cystatin C) against 51CrEDTA clearance in 113 adult overweight Caucasians with diabetes mellitus type 2 (DM2) and chronic kidney disease (CKD). The results of present study demonstrated that the simple cystatin C formula could be a useful tool for the evaluation of renal function in overweight patients with DM2 and impaired kidney function in daily clinical practice in hospital and especially in outpatients. Despite the advantages of the simple cystatin C formula, cystatin C-based equations cannot completely replace the “gold standard” for estimation of the GFR in a population of DM2 patients with CKD, but may contribute to a more accurate selection of patients requiring such invasive and costly procedures.

Serum creatinine level is the most commonly used indices for assessment of glomerular filtration rate (GFR), even though these indices have been shown to have some limitations in clinical practice. We investigated the diagnostic efficacy of serum cystatin C compared to that of serum creatinine levels and identified the relating factors associated with changes in serum cystatin C levels in gout patients with renal impairment. A total of 68 gouty patients with renal impairment were enrolled in this study. Diagnostic efficacy of serum cystatin C levels was evaluated through non-parametric receiver operating characteristic (ROC) analysis. The risk factors for changes in serum cystatin C levels were confirmed using multivariate regression analysis. With 24-hr urine creatinine clearance (Ccr) as the reference for GFR, 1/cystatin C (r=0.702, P<0.001) showed a significantly higher correlation with Ccr than 1/creatinine (r=0.665, P<0.001). Multivariate correlation analysis demonstrated that the clinical parameters for increased serum cystatin C are a higher stage of chronic kidney disease, older age, use of allopurinol, and lower high density lipoprotein-cholesterol. The area under the curve (AUC) at ROC plots identified that of serum cystatin C was significantly greater than that of serum creatinine (AUC 0.804 of cystatin C and AUC 0.745 of creatinine). The study suggests that serum cystatin C is a reliable endogenous marker for the assessment of renal function or GFR in gout patients with renal impairment.

OBJECTIVE

We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β-d-glucosaminidase [NAG], neutrophil gelatinase–associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid–binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR).

RESEARCH DESIGN AND METHODS

Damage markers were measured in triplicate in fresh morning urine samples and in plasma.

RESULTS

Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between −0.38 and −0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β −0.26; P = 0.037).

CONCLUSIONS

Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease.

Background

Cystatin C, an alternative serum measure of kidney function, is a stronger predictor of cardiovascular events than creatinine or estimated glomerular filtration rate (eGFR). We hypothesized that serum cystatin C concentration would have a stronger more linear association with cardiovascular functional status than creatinine-based measures in outpatients with established coronary heart disease (CHD).

Methods

We measured serum cystatin C, serum creatinine, and eGFR in 906 outpatients with established CHD. We examined the association of these 3 measures of kidney function with treadmill exercise capacity (metabolic equivalent tasks achieved) and heart rate recovery (HRR) between peak and 1 minute after exercise by using linear and logistic regression.

Results

Higher cystatin C concentrations were associated linearly with worse treadmill exercise capacity and HRR. The proportion of participants with poor exercise capacity (metabolic equivalent tasks achieved < 5) was 45% (99 of 222 participants) among those with cystatin C levels in the highest quartile (>1.30 mg/L) compared with 12% (29 of 241 participants) among those with cystatin C levels in the lowest quartile (<0.92 mg/L; adjusted odds ratio, 3.2; 95% confidence interval, 1.6 to 6.5; P = 0.001). The proportion of participants with poor HRR (<16 beats/min) was 42% (92 of 214 participants) among those with cystatin C levels in the highest quartile compared with 16% (37 of 238 participants) among those with cystatin C levels in the lowest quartile (adjusted odds ratio, 2.2; 95% confidence interval, 1.2 to 4.0; P = 0.01). The lowest quartile of eGFR (<61.8 mL/min [<1.03 mL/s]) was associated with decreased exercise capacity and prolonged HRR, but no difference was observed across the upper 3 quartiles of eGFR.

Conclusion

In patients with established CHD, cystatin C concentrations are associated linearly with worse exercise capacity and HRR. Cystatin C detects an association of impaired kidney function with decreased HRR and exercise capacity that is not fully captured using creatinine-based measurements.

Purpose of Review

To discuss recent studies which have evaluated determinants of cystatin C and to focus on the relationship of cystatin C with mortality, cardiovascular disease (CVD) and non-cardiovascular outcomes.

Recent Findings

In the Chronic Kidney Disease Epidemiology Study cystatin C was associated with demographic characteristics independent of measured glomerular filtration rate (GFR), although this was to a smaller extent than creatinine. In patients with established CKD, cystatin C was strongly and inversely correlated with measured GFR, suggesting that although cystatin C may have other determinants, it is primarily a measure of kidney function. Several cohort studies, particularly in older adults, have now demonstrated that cystatin C is linearly associated with mortality, CVD and non-CVD outcomes, whereas creatinine is primarily associated with risk in individuals with more advanced kidney disease. A recent study has also shown that changes in kidney function as ascertained by cystatin C, even within the relatively normal range, are associated with subsequent CVD and all-cause mortality among older adults.

Summary

Cystatin C appears to capture an association of mild kidney disease with increased risk of mortality, CVD and non-CVD outcomes. Future studies should evaluate whether cystatin C can improve medical decision-making and lead to favorable patient outcomes.

Background

Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk for cognitive impairment, but their joint association is unknown.

Study Design

Prospective cohort study.

Setting and Participants

A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS )REasons for Geographic And Racial Disparities in Stroke) study.

Predictors

Albuminuria was assessed by the urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (CKD Epidemiology Collaboration) equation.

Outcomes

Incident cognitive impairment was defined as a score of 4 or less on the Six-item Screener at the last follow-up visit.

Results

Over a mean follow-up of 3.8 ± 1.5 years, UACR 30 – 299 and ≥300 mg/g were independently associated with 31% and 57% higher risk for cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest among those with high eGFR and attenuated at lower levels (P=0.04 for trend). Relative an eGFR ≥60 ml/min/1.73m2, eGFR <60 ml/min/1.73m2 was not independently associated with cognitive impairment. However, after stratifying by UACR, eGFR <60 ml/min/1.73m2 was associated with 30% higher risk for cognitive impairment among participants with UACR <10 mg/g but not higher UACR levels (P=0.04 for trend).

Limitations

single measure of albuminuria and eGFR, screening test of cognition

Conclusions

When eGFR was preserved, albuminuria independently associated with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR independently associated with cognitive impairment. Albuminuria and low eGFR are complementary but not additive risk factors for incident cognitive impairment.

Background. It has been suggested that cystatin C may be a superior measure of estimated glomerular filtration rate (eGFR) than creatinine-based methods. We aimed to assess the utility of cystatin C for clinical triage in community-based settings.

Methods. We identified cystatin C thresholds that maximize sensitivity and specificity (MaxSn + Sp) for predicting death and subsequently applied classification tree methodology considering serum creatinine, creatinine-based eGFR, urinary albumin–creatinine ratio and conventional modifiable risk factors to define subgroups, interactions and hierarchical ranks in fasting US adults (National Health and Nutrition Examination Survey 1988–94, followed through 2006).

Results. A threshold cystatin C value of 0.94 mg/L exhibited the best maximum combined value of sensitivity and specificity for predicting death (MaxSn + Sp, Sn 0.64/Sp 0.78). When all variables were considered jointly in a classification tree, cystatin C and albumin–creatinine ratio were the primary mortality discriminators in subgroups that added up to 41 and 14% of the study population, respectively; serum creatinine and creatinine-based eGFR were non-discriminatory.

Conclusion. Cystatin C may be useful for risk-based clinical triage in public health settings.

Background

Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independent of conventional measures of renal function. We examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis.

Methods

We measured serum cystatin C, creatinine, TNF-α, IL-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR) and other clinical parameters in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models.

Results

Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than controls (1.09[Interquartile range, IQR: 0.85–1.28]mg/L vs. 0.89 [IQR: 0.76–0.99]mg/L; P<0.001 after adjusting for age, race and sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (P=0.04), ESR (P<0.001), CRP (P=0.04), TNF-α (P=0.008) and IL-6 (P=0.01) after adjustment for age, race and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, P= 0.31) and the association remained non-significant after adjustment for age, race, sex and Framingham risk score (P=0.99).

Conclusions

Cystatin C was higher in patients with SLE than control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.